SIRT6 promotes intrahepatic cholangiocarcinoma development by reprogramming glutamine metabolism via enhanced GLUL

作者：Mi Zhang, Chanyuan Chen, Haifeng Zhang, Tanqing Long, Tingjie Wang, Nanjin Ding, Ruitao Long, Hua Wu, Zhilu Ma, Zhongyu Cheng, Junyan Tao, Dong Kuang, Lei Li, Chuanrui Xu · 发表于：Gut · 年份：2025 · DOI：10.1136/gutjnl-2025-335729 · 被引用次数：7 · 研究领域：Sirtuins and Resveratrol in Medicine、Silymarin and Mushroom Poisoning、Cancer, Hypoxia, and Metabolism

BACKGROUND: SIRT6 acts as a tumour suppressor in multiple cancers by regulating glucose and lipid metabolism, but its role in intrahepatic cholangiocarcinoma (ICC) remains unclear. OBJECTIVE: We investigated the role and molecular mechanisms of SIRT6 in ICC development and progression. DESIGN: Spatial transcriptome and single-cell sequencing data from public ICC cohorts and clinical specimens were used to establish the clinical relevance of SIRT6 overexpression. B/R cell-established allografts and AKT/YAP-induced primary ICC mouse models were used to investigate the oncogenic role of SIRT6. The function of SIRT6 in metabolic regulation was assessed using seahorse analysis, metabolomics and isotope tracing. The transcriptional targets of SIRT6 were screened by RNA sequencing and confirmed by dual-luciferase assay and chromatin immunoprecipitation, and the molecular interactions and deacetylation activity of SIRT6 were analysed via co-immunoprecipitation. RESULTS: SIRT6 was highly expressed in both human and mouse ICC tissues and cell lines. SIRT6 knockdown significantly inhibited ICC cell growth in vitro and ICC development in mouse models. Hydrodynamic co-injection of SIRT6 and AKT resulted in ICC formation in mice. SIRT6 promoted glutamine synthesis by enhancing GLUL transcription and stabilising GLUL protein degradation. SIRT6 silencing decreased glutamine levels, subsequently reducing the levels of nucleotides and amino acids in ICC cells. Thus, SIRT6 or GLUL inhibitors ca...